Abstract
In most eukaryotes, the prophase of the first meiotic division is characterized by a high level of homologous recombination between homologous chromosomes. Recombination events are not distributed evenly within the genome, but vary both locally and at large scale. Locally, most recombination events are clustered in short intervals (a few kilobases) called hotspots, separated by large intervening regions with no or very little recombination. Despite the importance of regulating both the frequency and the distribution of recombination events, the genetic factors controlling the activity of the recombination hotspots in mammals are still poorly understood. We previously characterized a recombination hotspot located close to the Psmb9 gene in the mouse major histocompatibility complex by sperm typing, demonstrating that it is a site of recombination initiation. With the goal of uncovering some of the genetic factors controlling the activity of this initiation site, we analyzed this hotspot in both male and female germ lines and compared the level of recombination in different hybrid mice. We show that a haplotype-specific element acts at distance and in trans to activate about 2,000-fold the recombination activity at Psmb9. Another haplotype-specific element acts in cis to repress initiation of recombination, and we propose this control to be due to polymorphisms located within the initiation zone. In addition, we describe subtle variations in the frequency and distribution of recombination events related to strain and sex differences. These findings show that most regulations observed act at the level of initiation and provide the first analysis of the control of the activity of a meiotic recombination hotspot in the mouse genome that reveals the interactions of elements located both in and outside the hotspot.
Highlights
In most eukaryotes, the formation of at least one reciprocal exchange, or crossover (CO), per chromosome pair between nonsister chromatids provides the physical connection that is required for the segregation of homologous chromosomes at the first meiotic division
These double-strand break (DSB) are repaired by interactions with a nonsister chromatid, giving rise to two types of homologous recombination products, CO and gene conversion without associated crossover (NCO)
The initiation of recombination is activated by a haplotype-specific element, localized outside the hotspot and acting in trans
Summary
The formation of at least one reciprocal exchange, or crossover (CO), per chromosome pair between nonsister chromatids provides the physical connection that is required for the segregation of homologous chromosomes at the first meiotic division. Recombination is initiated by the formation of DNA double-strand breaks (DSBs), catalyzed by Spo11 [1] These DSBs are repaired by interactions with a nonsister chromatid, giving rise to two types of homologous recombination products, CO and gene conversion without associated crossover (NCO). Despite the fact that both events are initiated by Spo11-dependent DSBs, formations of CO and NCO have different genetic requirements and are thought to involve different molecular intermediates [2,3]. Both the distribution of DSBs and the local variation in the proportion of events giving rise to a CO contribute to the final distribution of CO along the genome. A number of other proteins involved in later steps in the process of meiotic recombination are structurally and functionally conserved [4,5]
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